Avaliação dos polimorfismos do gene BCL11A e dos genes de reparo de fita dupla do DNA, ATM e ATR, em pacientes com Anemia Falciforme

• Ano de defesa: 2018
• Autor(a) principal: Cavalcante, Islara Rodrigues
• Orientador(a): Lemes, Romélia Pinheiro Gonçalves
• Tipo de documento: Dissertação
• Tipo de acesso: Acesso aberto
• Idioma: por
• Palavras-chave em Português: Anemia Falciforme; Gene BCL11A; Gene ATR; Polimorfismo Genético
• Link de acesso: http://www.repositorio.ufc.br/handle/riufc/39362

Sickle cell anemia is a monogenic disease caused by a point mutation in the β-globin gene that results in the production of an abnormal hemoglobin S (HbS) in homozygous. PA is characterized by a chronic inflammatory process, increased oxidative stress, and increased cell turnover in the bone marrow, which together with hypoxia have been associated with genetic instability and function as a risk factor for the development of genetic alterations. This instability may arise from a resistance to hypoxia-mediated apoptosis and / or compromised DNA repair mechanisms, leading to increased mutagenesis rates. Thus, two protein kinases the mutated telangiectasia ataxia (TMJ) and related ataxia telangiectasia Rad3 (ATR) play an important role, since they participate in the mechanism of repair of double-stranded DNA damage. The main pharmacological agent used in AF is Hydroxyurea (HU), which increases the concentration of fetal hemoglobin (HbF), a clinical modulator of the disease. An important gene associated with HbF expression is the BCL11A gene whose polymorphisms are associated with variations in HbF concentrations, which may minimize clinical events associated with the disease. In this context, the study aimed to evaluate the polymorphisms of BCL11A gene and double-tape repair genes (ATM and ATR), associating them with laboratory and clinical data of patients with FA. This is a cross-sectional, analytical study with 125 patients with clinical and molecular diagnosis of AF, with and without HU and baseline. Statistical analyzes were performed using software SPSS version 20 and values of p <0.05 were considered statistically significant. The mean age was 33 years, the majority being female. The mean corpuscular volume (CVM) and mean corpuscular hemoglobin (HCM) were higher (p <0.001) in patients without HU, whereas leukometry and neutrophils were lower (p = 0.029) and there was an association with lower limb ulcer (MMI). In the analysis of BCL11A polymorphism, rs7557939, there was a decrease in HbF (p = 0.0038), VCM (p <0.001) and HCM (p = 0.030) in patients with A / A genotype. Covariance analysis revealed an association between HbF, VCM and HCM, and HU treatment (p <0.05). The univariate analysis showed an association with the presence of MMI ulcer and the multivariate nominal regression analysis showed that patients with the A / G genotype were less likely to present an ulcer (p = 0.037) and that the A / A genotype correlated with the increase the chance of developing painful seizures (p <0.001). In the analysis of rs4671393, it was verified that the patients with the A / A genotype showed a higher number of leukocytes (p = 0.019) and platelets (p = 0.027). The analysis on rs1186868 showed no influence on the analyzed parameters. Regarding analyzes of DNA repair gene polymorphisms, the rs228593 gene polymorphism of the ATM gene revealed a decrease in the levels of HbS (p = 0.023) and platelet count (p = 0.018) in patients who presented the G / A genotype and A / A. In contrast, an increase in HbF (p = 0.010) was found in these same patients. The analysis of rs229032 polymorphism of the ATR gene showed no association with laboratory and clinical parameters. Thus, we can conclude that both the BCL11A gene polymorphism and the ATM gene polymorphism had influence as clinical and laboratory modulators in FA.